The long-term objective of this research is to understand the molecular mechanisms governing the regulation of innate immunity during aging in Drosophila melanogaster. More specifically, the proposed study will determine the role of a family of recently discovered antioxidant enzymes - peroxiredoxins - in regulating the immune system and to determine how this regulation relates to the aging process. Peroxiredoxins are known to be important in protecting cells against oxidative insult and the results of recent studies indicate that they are also involved in modulation of the immune system. The experimental strategy for the proposed research will be to determine the functional significance of individual peroxiredoxin genes primarily by manipulating the levels of peroxiredoxin expression. The inhibition of peroxiredoxin gene expression will be achieved by RNA interference and/or through the use of mutant alleles obtained by standard genetic approaches. Enhancement of peroxiredoxin activity will be achieved by transgenic methodology. The effects of the expression of peroxiredoxins on the inducibility of antimicrobial peptides and sensitivity of Drosophila to infection will be determined using molecular, biological, and bacteriological techniques. In addition, regulation of the immune system by peroxiredoxins will be assessed as a function of age. The results of this study will i) provide a direct test of the role of peroxiredoxin genes in innate immunity, and ii) permit the assessment of the interrelationship between the regulation of innate immunity and aging. This will set the stage for a more thorough investigation of the molecular underpinnings of innate immunity during aging.